The present invention relates to an agent for the prophylaxis or treatment of renal diseases, which comprises a compound having a Rho kinase inhibitory activity.
Renal diseases include a disease wherein hematuria and proteinuria are developed by various causes, and a disease wherein kidney function becomes low to develop acute or chronic renal failure that requires dialysis as the occasion demands. Many renal diseases are difficult to treat and prognosis is poor, and not a small number thereof proceed to terminal renal failure. In addition, renal diseases tend to increase with aging, where marked increase in the number of dialysis patients and aging of dialysis patients pose a significant medical and therapeutic problem of renal diseases.
In recent years, any progressive renal diseases including glomerulonephritis are said to show, in the course of developing a terminal renal failure, a significant disease state with concomitant fibrosis of renal interstitium, (Igaku no ayumi, Vol. 190 No. 1, 1999). Furthermore, many researchers have pointed out a clear correlation between interstitial fibrosis lesion obtained from the renal biopsy tissue of glomerulonephritis patients, and renal function or prognosis.
Accordingly, renal fibrosis has drawing attention as a universal treatment target for a renal disease that resists treatment.
At present, various investigations of the mechanism of glomerular inflammation causing interstitial inflammations, and further fibrosis are ongoing. It is considered that tubular epithelial cells are activated by a high urinary protein, components contained therein, such as a complement, a lipoprotein and ferritin, and inflammatory cytokines (IL-1xcex2, TNF-xcex1 etc.) produced and released in glomerulus, and the epithelial cells themselves produce cell adhesion molecules such as chemokine (e.g., MCP-1, RANTES etc.), integrin, VCAM-1, ICAM-1, selectin, osteopontin and the like to promote cellular infiltration. The infiltrated monocyte and T lymphocyte secrete new cytokines that act on tubular epithelial cells and infiltrated cells. Fibroblast is considered to be involved in such inflammatory lesion. In addition, cells having the characteristics of blood vessel smooth muscle, which is called myofibroblast (myoFb), are occasionally found. It is postulated that, in such interstitial lesion, extracellular matrices, such as type I and type III collagen, fibronectin and proteoglycan, are accumulated along with the destruction and atrophy of existent structures, and cell loss occurs due to apoptosis, which completes a renal fibrosis lesion.
On the other hand, as a compound having a Rho kinase inhibitory activity, a compound of the formula (I) to be mentioned later has been reported (WO98/06433). Certain isoquinolinesulfonamide derivative and isoquinoline derivative are also reported to show a Rho kinase inhibitory activity (WO98/06433 and Naunyn-Schmiedeberg""s Archives of Pharmacology 385(1) Suppl., R219, 1998). Furthermore, it has been reported that ethacrynic acid, certain vinyl benzene derivatives such as 4-[2-(2,3,4,5,6-pentafluorophenyl)-acryloyl]cinnamic acid and the like and cinnamic acid derivative have a Rho kinase inhibitory activity (WO00/57914, JP-A-2000-44513).
The pharmaceutical use of a compound having a Rho kinase inhibitory activity is disclosed in WO98/06433, and described to be widely useful as a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a cerebrovascular spasm suppressant, a therapeutic agent of asthma, a therapeutic agent of peripheral circulatory disturbance, a premature delivery preventive, a therapeutic agent of arterial sclerosis, an anticancer drug, an anti-inflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune diseases, an anti-AIDS agent, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy, a cerebral function improver, a contraceptive drug, and a gastrointestinal tract infection preventive.
Furthermore, the compound of formula (I) has been already known to be useful as an agent for the prophylaxis or treatment of disorders of circulatory organs such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and WO95/28387).
The isoquinolinesulfonamide derivative described in the above-mentioned WO98/06433 is known to be effective as a vasodilating agent, a therapeutic agent of hypertension, a cerebral function improver, an anti-asthma agent, a heart protecting agent, a platelet aggregation inhibitor, a therapeutic agent of neurologic manifestation, an anti-inflammatory agent, an agent for the prevention and treatment of hyperviscosity syndrome, a therapeutic agent of glaucoma, a diminished tension agent, a motor paralysis improver of cerebral thrombosis, an agent for prevention and treatment of virus infection and transcriptional control factor inhibitor (JP-A-57-200366, JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-56668, JP-A-6-80569, JP-A-6-293643, JP-A-7-41424, JP-A-7-277979, WO97/23222, JP-A-9-227381, JP-A-10-45598 and JP-A-10-87491).
Moreover, the isoquinoline derivative described in the above-mentioned publication (Naunyn-Schmiedeberg""s Archives of Pharmacology 385(1) Suppl., R219, 1998) is known to be useful as an agent for the prevention and treatment of brain tissue disorder due to vasospasm (WO97/28130).
However, compounds having Rho kinase inhibitory activity are not reported to be useful for renal diseases.
The present invention aims at solving the above-mentioned problems and provides a novel agent for the prophylaxis or treatment of renal diseases.
In an attempt to solve the above-mentioned problems, the present inventors have conducted intensive studies and found that a compound having a Rho kinase inhibitory activity shows a renal interstitial fibrosis inhibitory action, and therefore, is useful as a prophylactic and therapeutic agent of renal diseases, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) An agent for the prophylaxis or treatment of a renal disease, which comprises a compound having a Rho kinase inhibitory activity.
(2) The agent for the prophylaxis or treatment of a renal disease of (1) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I) 
wherein
Ra is a group of the formula 
in the formulas (a) and (b),
R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or a group of the formula 
xe2x80x83wherein R6 is hydrogen, alkyl or formula: xe2x80x94NR8R9 wherein R8 and R9 are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, R7 is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R6 and R7 in combination show a group forming a heterocycle optionally further having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
or R and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally further having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl or azide, and
A is a group of the formula 
xe2x80x83wherein R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and 1, m and n are each 0 or an integer of 1-3,
in the formula (c),
L is hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl, tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or a group of the formula 
wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxyalkyl, alkoxycarbonylalkyl, xcex1-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl,
Q1 is hydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl,
W is alkylene,
Q2 is hydrogen, halogen, hydroxy or aralkyloxy,
X is alkylene,
Q3 is hydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl;
and Y is a single bond, alkylene or alkenylene, and
in the formula (c),
a broken line is a single bond or a double bond, and
R5 is hydrogen, hydroxy, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy;
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(3) The agent for the prophylaxis or treatment of a renal disease of (1) or (2) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (Ixe2x80x2) 
wherein
Raxe2x80x2 is a group of the formula 
xe2x80x83wherein
Rxe2x80x2 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or Rxe2x80x2 and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally further having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl or azide, and
A is a group of the formula 
xe2x80x83wherein R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and 1, m and n are each 0 or an integer of 1-3,
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(4) The agent for the prophylaxis or treatment of a renal disease of (1), wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof, especially (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(5) The agent for the prophylaxis or treatment of a renal disease of any of (1) to (4) above, wherein the renal disease accompanies renal fibrosis.
(6) The agent for the prophylaxis or treatment of a renal disease of (5) above, wherein the renal disease accompanying renal fibrosis is interstitial renal fibrosis.
(7) A pharmaceutical composition for the prophylaxis or treatment of renal disease, which comprises a compound having a Rho kinase inhibitory activity and a pharmaceutically acceptable carrier.
(8) The pharmaceutical composition for the prophylaxis or treatment of renal disease of (7) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(9) The pharmaceutical composition for the prophylaxis or treatment of renal disease of (7) or (8) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(10) The pharmaceutical composition for the prophylaxis or treatment of renal disease of (7) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)-cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof, especially (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(11) The pharmaceutical composition for the prophylaxis or treatment of renal disease of any of (7) to (10) above, wherein the renal disease accompanies renal fibrosis.
(12) The pharmaceutical composition for the prophylaxis or treatment of renal disease of (11) above, wherein the renal disease accompanying renal fibrosis is interstitial renal fibrosis.
(13) A method of the prophylaxis or treatment of renal disease, which comprises administering a pharmaceutically effective amount of a compound having a Rho kinase inhibitory activity to a patient.
(14) The method of the prophylaxis or treatment of renal disease of (13) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(15) The method of the prophylaxis or treatment of renal disease of (13) or (14) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(16) The method of the prophylaxis or treatment of renal disease of (13) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof, especially (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(17) The method of the prophylaxis or treatment of renal disease of any of the above-mentioned (13)-(16), wherein the renal disease accompanies renal fibrosis.
(18) The method of the prophylaxis or treatment of renal disease of (17) above, wherein the renal disease accompanying fibrosis is interstitial renal fibrosis.
(19) Use of a compound having a Rho kinase inhibitory activity for the production of an agent for the prophylaxis or treatment of a renal disease.
(20) The use of (19) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I), especially formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(21) The use of (19) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof, especially (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(22) The use of any of (19) to (21) above, wherein the renal disease accompanies renal fibrosis.
(23) The use of (22) above, wherein the renal disease accompanying renal fibrosis is interstitial renal fibrosis.
(24) A commercial package comprising a pharmaceutical composition for the prophylaxis or treatment of renal disease of any of (7) to (12) above, and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the prophylaxis or treatment of renal disease.